JP2013544842A - Compounds and methods for skin repair - Google Patents

Abstract

The present disclosure provides compositions and methods for treating skin defects. The composition comprises a therapeutically effective amount of the compound useful for treating skin defects such as wounds, scars, and wrinkles.
[Selection] Figure 1

Description

Cross-reference to related applications This application claims the benefit of US Provisional Application No. 61 / 419,115, filed Dec. 2, 2010, which is incorporated herein by reference in its entirety.

  The present invention relates generally to compositions and methods for wound healing, and specifically to the use of EP4 agonists for treatment in wound healing, scar reduction, and skin repair.

  Prostanoid EP4 receptor is a G protein-coupled receptor that mediates the action of prostaglandin E2 (PGE2) and is characterized by the longest intracellular C-terminal loop compared to other prostanoid receptors. EP4 receptors not only couple G to mediate increases in cAMP concentrations, but also couple to Gi and phosphorylate key intracellular signaling proteins such as ERK or AKT. EP2 is another PGE2 receptor subtype similar to EP4. Several functions overlap between the EP2 and EP4 receptors. For example, any of these receptors induces IOP reduction and participates in PGE2-mediated RANKL via cAMP signaling. However, some functions are different, mainly due to differences in receptor density at the target site. Thus, EP2 is involved in cumulus expansion during ovulation and fertilization, and EP4 controls the closure of the arterial duct. When these receptors are involved in ovulation and fertilization, induce bone formation, protect against inflammatory bowel disease, promote Langerhans cell migration and maturation, and mediate joint inflammation, especially in models of collagen-induced arthritis EP4 receptor expression is regulated by a variety of physiological and pathophysiological processes.

  Scars from cosmetic surgery, including but not limited to shallow wounds, scars from back, mid-chest, heart, abdomen, pubic, and joint surgery, scars from burns, aging, and UV aging, and wrinkles Such skin defects can occur on any area of the body. Scarring can occur in all parts of the adult body after local or systemic trauma such as mechanical injury, surgery, burns, chemical contact, radiation, and addiction, and is normal at the wound site Represents the failure of the homeostasis process to restore structure. Wrinkles occur for a variety of reasons and are a common sign of aging. Both scarring and signs of aging can typically be considered undesirable. In addition, prevention in people at high risk of having unsightly or severe scars resulting from some injury is highly desirable.

  Therefore, agents that treat or prevent such skin defects safely and effectively are highly desirable.

  The present disclosure provides compositions and methods for wound healing and scar reduction. The compositions and methods of the present invention comprise at least one EP4 agonist as described herein. Wounds, scars, and other skin defects that can be treated or prevented using the compositions and methods of the present invention include surgery, trauma, disease, mechanical injury, burns, radiation, poisoning in all parts of the body , May be caused by events such as UV aging, aging, contact with chemicals.

  In one embodiment of the present invention, a method for treating a skin defect is provided. Such methods include, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one EP4 agonist or EP4 / EP2 dual agonist or a combination of EP4 and EP2 agonists. Can be performed, thereby treating skin defects.

In one embodiment, a method for healing a wound is provided, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound having the structure: ,
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof Yes, n is 0-7, and X is S or O.

In another embodiment, a method for treating a shallow wound is provided, the method comprising administering a composition comprising a therapeutically effective amount of a compound having the structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof And n is 0-7, X is S or O,
Wounds heal more normally than without administration of the composition.

In yet another embodiment, a method of reducing the appearance of wrinkles comprises administering to the wrinkles a composition comprising a therapeutically effective amount of a compound having the structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof And n is 0-7, X is S or O,
The appearance of wrinkles is reduced.

In another embodiment, the composition of the invention comprises at least one EP4 agonist having the structure:
Where
Each of Z _{1 to} Z ₆ is independently C, N, O, or S;
A is — (CH ₂ ) ₆ — or cis —CH ₂ CH═CH— (CH ₂ ) ₃ —, and one or two carbons may be substituted with S or O, or A Is — (CH ₂ ) _m —Ar— (CH ₂ ) _o —, wherein Ar is arylene or heteroarylene, and the sum of m and o is 1-4, and one CH ₂ May be substituted with S or O;
R ₁ is H, alkyl, cycloalkyl, oxyalkyl, hydroxyalkyl, alkenyl, oxyalkenyl, or hydroxyalkenyl,
R ₂ is alkyl, hydroxyl, halide, or oxo;
J is alkylene, cycloalkylene, oxyalkylene, hydroxyalkylene, fluoroalkylene, difluoroalkylene;
E is C _1-12 alkyl, R ₃ , or —Y—R ₃ , wherein Y is CH ₂ , S, or O, R ₃ is aryl or heteroaryl,
n is 0 or 1,
The dotted line represents the presence or absence of a bond.

3 is an image of a skin biopsy sample stained with hematoxylin and eosin (H & E) 3 days after skin incision. The image shows the epidermal coverage of the wound site (200x magnification). FIG. 2 is a graph showing epidermal defects (μm and percentage) on days 2 and 3 after surgery for a group treated with vehicle and a group treated with Compound 1. FIG. Epidermis thickness of wound sites at 7 days and 14 days after surgery in the vehicle treated group and Compound 1 treated group compared to the surrounding normal site (ratio of wound site / normal site) It is a graph to show. FIG. 5 is a graph showing quantification of neutrophils (s / hf) at the wound sites on the second and third days after surgery in the vehicle treated group and the compound 1 treated group. Neutrophils in the dermis area were counted under 400X magnification. FIG. 2 is an image (6.5 × magnification) showing the macroscopic appearance of a skin wound site 14 days after surgery in skin treated with vehicle and skin treated with Compound 1. FIG. 2 is a graph quantifying skin scar tissue sections and overall tissue appearance of samples treated with either vehicle or Compound 1. FIG. FIG. 6A shows the scar width (μm) of the upper, middle and lower Masson trichrome stained sections of the section. FIG. 6B shows the overall skin wound score on days 3, 7, and 14 after surgery. FIG. 6 is a graph quantifying the width of skin scars on a wound section 2 weeks after surgery. FIG. 7A shows the scar width (μm) of the upper, middle and lower Picrosirius red stained sections. FIG. 7B shows the scar width of the upper, middle, and lower sections of Masson Trichrome stained sections treated with either vehicle, TGF-β3, or Compound 1. FIG. 6 is a graph quantifying the width of skin scars in tissues treated with vehicle, TGF-β3, or Compound 1 70 days after surgery based on Masson trichrome staining.

  It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” and other forms such as “included” and “included” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

  Unless specific definitions are provided, the nomenclature and experimental procedures and techniques utilized in connection with the analytical, synthetic organic, and synthetic inorganic chemistry described herein are those known in the art. It is. Standard chemical symbols are used synonymously with the formal names represented by such symbols. Thus, for example, the terms “hydrogen” and “H” are understood to have the same meaning. Standard techniques may be used for chemical synthesis, chemical analysis, and formulation.

As used herein, “alkyl” refers to a straight or branched hydrocarbyl group having from 1 to up to about 100 carbon atoms. Whenever appearing herein, a numerical range such as “1-100” or “C ₁ -C ₁₀₀ ” refers to each integer within a given range, for example, the term “alkyl” Although the numerical range of atoms is not specified, “C ₁ -C ₁₀₀ alkyl” means that the alkyl group has only one carbon atom, only two carbon atoms, only three carbon atoms, etc. It means that it may contain carbon atoms (including 100). “Substituted alkyl” is alkyl, alkenyl, alkynyl, hydroxy, oxo, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, haloalkyl, cyano, nitro, nitrone, amino, lower alkylamino, lower alkyldiamino, amido, azido, -C (O) H, -C (O) R 7, -CH 2 OR 7, -C (O) —, —C (O) —, —S—, —S (O) ₂ , refers to an alkyl moiety carrying a substituent comprising —OC (O) —O—, wherein R ₇ is H, or lower alkyl, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl and the like. As used herein, “lower alkyl” refers to an alkyl moiety having from 1 to about 6 carbon atoms.

  As used herein, “alkenyl” is a straight or branched chain hydrocarbyl having at least one carbon-carbon double bond and having in the range of about 2 up to about 100 carbon atoms. A “substituted alkenyl” refers to an alkenyl group bearing one or more substituents as described above. As used herein, “lower alkenyl” refers to an alkenyl moiety having from 2 to about 6 carbon atoms.

  As used herein, “alkynyl” is a straight or branched hydrocarbyl group having at least one carbon-carbon triple bond and having in the range of about 2 up to about 100 carbon atoms. “Substituted alkynyl” further refers to an alkynyl group bearing one or more substituents as described above. As used herein, “lower alkynyl” refers to an alkynyl moiety having 2 to about 6 carbon atoms.

  As used herein, “cycloalkyl” refers to a cyclic (ie, containing a ring) alkyl moiety, typically containing from about 3 up to about 8 carbon atoms in the range “substituted”. “Cycloalkyl” further refers to a cycloalkyl group bearing one or more substituents as described above.

  As used herein, “aryl” refers to an aromatic group having from 5 to up to 14 carbon atoms, and “substituted aryl” further carries one or more substituents as described above. Refers to an aryl group.

  As used herein, “heteroaryl” contains one or more heteroatoms (eg, N, O, S, etc.) as part of the ring structure and a total of 5 to 5 within the ring structure. Refers to an aromatic moiety having up to 14 atoms (ie, carbon and heteroatoms). “Substituted heterocycle” further refers to a heterocycle group bearing one or more substituents as described above.

  As used herein, a “heterocycle” contains one or more heteroatoms (eg, N, O, S, etc.) as part of the ring structure and is within the range of 3 to up to 14 A non-aromatic cyclic (ie, containing a ring) group having 5 carbon atoms, and “substituted heterocycle” further refers to a heterocyclic group bearing one or more substituents as described above.

  As used herein, “halogen” or “halide” refers to fluoride, chloride, bromide, or iodide. “Fluoride, chloride, bromide, or iodide” may be referred to as “fluoro, chloro, bromo, or iodo”.

  As used herein, an “ene” suffix is attached to two other parts of a molecule when added to the end of a term such as, for example, “alkyl” (to become “alkylene”). The two moieties are bonded to two distinctly different alkyl moieties. That is, the alkyl moiety occupies an internal position of the molecule.

Disclosed herein are compositions and methods for wound healing and scar reduction. In one embodiment, a composition described herein comprises a compound having the following general structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof Yes, n is 0-7, and X is S or O.

In certain embodiments, R ⁴ is H, R ³ is H, and X is S.

In another embodiment, R ¹ and R ² are CH ₃ .

In a further embodiment, R ⁵ is Cl.

In yet another embodiment, the compound is:

In another embodiment, the method of the invention employs a composition comprising at least one EP4 agonist having the structure:
Where
Each of Z _{1 to} Z ₆ is independently C, N, O, or S;
A is — (CH ₂ ) ₆ — or cis —CH ₂ CH═CH— (CH ₂ ) ₃ —, wherein one or two carbons may be substituted with S or O; Or A is — (CH ₂ ) _m —Ar— (CH ₂ ) _o —, wherein Ar is arylene or heteroarylene, and the sum of m and o is 1 to 4; Two CH ₂ may be replaced by S or O;
R ₁ is H, alkyl, cycloalkyl, oxyalkyl, hydroxyalkyl, alkenyl, oxyalkenyl, or hydroxyalkenyl,
R ₂ is alkyl, hydroxyl, halide, or oxo;
J is alkylene, cycloalkylene, oxyalkylene, hydroxyalkylene, fluoroalkylene, difluoroalkylene;
E is C _1-12 alkyl, R ₃ , or —Y—R ₃ , wherein Y is CH ₂ , S, or O, R ₃ is aryl or heteroaryl,
n is 0 or 1,
The dotted line represents the presence or absence of a bond.

In another embodiment of the present invention, a method for treating a skin defect is provided, the method comprising administering a composition comprising a therapeutically effective amount of at least one compound having the structure: including.

In another embodiment of the present invention, a method for treating a skin defect is provided, the method comprising administering a composition comprising a therapeutically effective amount of at least one compound having the structure: including.

In another embodiment of the present invention, a method for treating a skin defect is provided, the method comprising administering a composition comprising a therapeutically effective amount of at least one compound having the structure: including.

In another embodiment, the method of the invention employs a composition comprising at least one EP4 agonist having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof,
Where
A ¹ , A ² , A ³ , and A ⁴ are C, N, CR ^A , NR ^A , C- (O) R ^A , N- (O) R ^A , C- (R ^A R ^B ), respectively. And N- (R ^A R ^B )
R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each a bond, H, halo, cyano, nitro, oxo, CF ₃ , OCF ₃ , C 1-5 alkyl, C 2-8 alkenyl, C 2-8 alkynyl. , C1-8 hydroxyalkyl, C1-8 haloalkyl, C _{3 ~ 10} cycloalkyl, C _{4 to 10} heterocycloalkyl, C3～10 cycloalkoxy, C1-8 alkoxy, C1-8 alkoxyalkyl, C _{5 to 10} aryl, And C _5-10 heteroaryl independently selected from the above, C 1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C _3-10 cycloalkyl, C _{4 to 10} heterocycloalkyl, C _{3 to 10} cycloalkoxy, C1-8 alkoxy, C1-8 alkoxyalkyl, C _{5 to 10} aryl, and C5~1 Each heteroaryl moiety, ^{optionally, R A, R A R B} , CR A, CR A R B, SR A, SR A R B, OR A, COR A, S (O) a R A, NR ^A R ^B , CONR ^A R ^B , N (O) R ^A R ^B , (CR ^A R ^B ) _b (C _{5 to} io aryl), (CR ^A R ^B ) _b (C _{5 to} io heteroaryl), Or substituted by one or more of (CR ^A R ^B ) _b (C _3-10 cycloalkyl)
R ^A and R ^B are each a bond, H, halo, cyano, nitro, oxo, CF ₃ , OCF ₃ , C 1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _5-10 aryl, C _{5 10} heteroaryl, arylalkyl, C _{3 to 10} cycloalkyl, C _{4 to 10} heterocycloalkyl, C _{3 to 10} cycloalkoxy, are independently selected from C1~8 alkoxy, and C _{2 to 8} alkoxyalkyl,
D ¹ is C, N, O, S, CR ^A , NR ^A , OR ^A , SR ^A , C- (O) R ^A , N- (O) R ^A , C- (O) OR ^A , N- (O) OR ^A , C- (R ^A R ^B ), N- (R ^A R ^B ), or S- (R ^A R ^B ), each a being 0, 1, 2, 3, 4 , And 5 and each b is independently selected from 0, 1, 2, 3, 4, and 5.

In another embodiment, the method of the invention employs a composition comprising at least one EP4 agonist having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof,
Where
A ⁵ , A ⁶ , A ⁷ , and A ⁸ are C, N, CR ^C , NR ^C , C- (O) R ^C , N- (O) R ⁰ , C- (R ⁰ R ⁰ ), And N- (R ⁰ R ⁰ ) and
R ⁶ and R ⁷ are each a bond, H, halo, cyano, nitro, oxo, CF ₃ , OCF ₃ , C 1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C 1-8 hydroxyalkyl, C 1 8 haloalkyl, C _{3 to 10} cycloalkyl, C _{4 to 10} heterocycloalkyl, C _{3 to 10} cycloalkoxy, C1-8 alkoxy, C1-8 alkoxyalkyl, C _{5 to 10} aryl, and C _{5 to 10} heteroaryl independently selected from the C1-8 alkyl, C _{2 to 8} alkenyl, C _{2 to 8} alkynyl, C1-8 hydroxyalkyl, C1-8 haloalkyl, C _{3 to 10} cycloalkyl, C _{4 to 10} heterocycloalkyl , C _{3 to 10} cycloalkoxy, C1-8 alkoxy, C1-8 alkoxyalkyl, its C _{5 to 10} aryl, and C5~10 heteroaryl moiety Re is ^{optionally, R c, R C R D} , CR C, CR C R D, NR C, OR C, SR C, SR C R D, COR C, S (O) n R 0, NR ^C R ^D , CONR ⁰ R ⁰ , N (O) R ⁰ R ⁰ , (CR ⁰ R ⁰ ) _m (C _5-10 aryl), (CR ⁰ R ⁰ ) _m (C _5-10 heteroaryl), or Substituted with one or more of (CR ^c R °) _m (C _3-10 cycloalkyl), R ⁸ is H, halo, cyano, nitro, oxo, CF ₃ , OCF ₃ , C 1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C 1-5 hydroxyalkyl, C 1-8 haloalkyl, C _3-10 cycloalkyl, C _4-10 heterocycloalkyl, C _3-10 cycloalkoxy, C 1-5 alkoxy, C1-8 alkoxyalkyl, C5-10 aryl, or C5-10 heteroaryl. ,
R ⁹ is, H, halo, cyano, nitro, oxo, a CF _3, OCF _3, R ¹⁰ is, H, halo, cyano, nitro, _{oxo, CF 3, OCF 3, Ci} ~8 alkyl, _{C. 2 to 8} alkenyl, C _2-8 alkynyl, Ci ₈ hydroxyalkyl, Ci ₈ haloalkyl, C ₃ i ₀ cycloalkyl, C ₄ i ₀ heterocycloalkyl, C ₃ i ₀ cycloalkoxy, Ci ₈ alkoxy, ci _{to 8} alkoxyalkyl, a _{C. 5 to} io aryl or C5~10 heteroaryl,
R ¹¹ is a bond, oxo, R °, OR ⁰ , Ci ₈ alkyl, C _2-8 alkenyl, C _2-8 alkynyl, Ci ₈ hydroxyalkyl, Ci ₈ haloalkyl, C ₃ i ₀ cycloalkyl, _{C. 4 to} i ₀ heterocycloalkyl, _{C. 3 to} i ₀ cycloalkoxy, Ci _{to 8} alkoxy, Ci _{to 8} alkoxyalkyl, a _{C. 5 to} io aryl or C _{5 to 10} heteroaryl, said Ci _{to 8} alkyl, C _{2 to 8} alkenyl, C _{2 to 8} alkynyl, Ci _{to 8} hydroxyalkyl, Ci _{~ 8} haloalkyl, _{C. 3 to} i ₀ cycloalkyl, _{C. 4 to} i ₀ heterocycloalkyl, _{C. 3 to} i ₀ cycloalkoxy, Ci _{~ 8} alkoxy, Ci _{to 8} alkoxyalkyl, each of the _{C. 5 to} io aryl, and _{C. 5 to} io heteroaryl moiety, ^{optionally, CR 0, CR 0 R 0} , SR 0 ^{SR 0 R 0, OR 0,} COR 0, S (O) m R °, NR 0 R 0, CONR 0 R 0, N (O) R 0 R 0, (CR c R 0) m (C 5~ io Aryl), (CR ^c R ⁰ ) _m (C ₅ -io heteroaryl), or (CR ° R ⁰ ) _m (C ₃ -i ₀ cycloalkyl)
R ^c and R ^D is a bond, H, halo, cyano, nitro, _{oxo, CF 3, OCF 3, Ci} ~8 alkyl, _{C. 2 to} 8 alkenyl, _{C. 2 to} 8 alkynyl, _{C. 5 to} io aryl, C ₅ selection _~ io heteroaryl, arylalkyl, _{C. 3 to} i ₀ cycloalkyl, _{C. 4 to} i ₀ heterocycloalkyl, _{C. 3 to} i ₀ cycloalkoxy, Ci _{to 8} alkoxy, and C _2～S independently alkoxyalkyl And
D ² is, C, N, O, S , CR C, NR C, OR C, SR C, C- (O) R 0, N- (O) R 0, C- (O) OR 0, N- (O) OR ⁰ , C- (R ⁰ R ⁰ ), N- (R ⁰ R ⁰ ), or S- (R ⁰ R ⁰ ), each m being O, 1, 2, 3, 4 And 5, each n is independently selected from O, 1, 2, 3, 4 and 5.

In another embodiment, the method of the invention comprises at least one EP4 agonist having the structure:
Or a composition comprising a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or a mixture thereof,
Where
R and R4 independently represent H or C1-6 alkyl;
R 1 independently represents hydrogen, C 1-6 alkyl, halogen, CF 3, aryl, wherein the aryl optionally has 1-3 halogen groups, Q-6 alkyl groups, CF 3 groups, or N ( R4) substituted with 2 groups,
R2 represents H or halogen;
R3 represents COOR or carboxylic acid isostere;
n represents 0 to 3,
-Represents a double bond or a single bond.

In another embodiment, the method of the invention comprises at least one EP4 agonist having the structure:
Or a composition comprising a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or a mixture thereof, wherein
Z1 represents C-W1 or N;
W, W1, and X are independently H, NR4R4, or halogen;
Y represents hydrogen, halogen, C1-4 alkoxy, C1-4 alkyl, C2-4 alkenyl, aryl, heterocyclyl, C3-6 cycloalkyl, NO2, or CF3, wherein the alkyl, alkenyl, aryl, and heterocyclyl are Optionally substituted with 1 to 3 groups;
R1 and R2 are independently H, halogen, or C1-4 alkyl,
Alternatively, R1 and R2 are optionally joined together and a 3-5 membered carbocycle optionally interrupted by 1-2 heteroatoms selected from O, S, SO, SO2, and N9. May form,
R3 represents R1 or OH, or R3 and R1 bonded to the same carbon may form a carbonyl group;
Q is CO2R4, tetrazolyl, SO3R4, -CF2SO2NH2, -SO2NH2, CONHSSO2R5, SO2NHCOR7, -PO (OH) 2, CONHP02R6, CONHRd, -COCH2OH, or a heterocyclyl containing an acidic hydroxyl group, Unsubstituted or substituted with three R1O groups;
Ar1 represents phenyl, pyridinyl, or thienyl, provided that the two substituents (CRιR2) n and (CRιR2) m with respect to phenyl and pyridinyl are para to each other, or the 2-position and 5 of thienyl The Ari is optionally substituted with 1 to 3 R1O groups, provided that
Ar2 represents 2,1,3-benzooxadiazol-5-yl, phenyl, pyridyl, or thienyl, optionally halogen, -6 alkyl, OC1-6 alkyl, CO2H, SC1-6 alkyl, Substituted with 1 to 3 groups selected from CF3, OCF3, and SCF3;
R4 represents H or C1-6 alkyl;
R5, R6, R7, and R8 represent C1-6 alkyl, CF3, aryl, heteroaryl, heterocyclyl, Z-aryl, or Z-heteroaryl, wherein the aryl, heteroaryl, heterocyclyl is represented by 1 to 3 Unsubstituted or substituted with an R1O group,
Z is an optional linker containing 0-4 carbon atoms optionally substituted with C1-4 alkyl;
R9 represents hydrogen, C1-6 alkyl, wherein the alkyl is optionally substituted with 1 to 3 halogens, CN, OH, C1-6 alkoxy, C1-4 acyloxy, or amino;
R1O is halogen, C1-6 alkoxy, C1-6 alkyl, CF3, cyano, aryl, heteroaryl, heterocyclyl, SC1-6 alkyl, SC6-10 aryl, SC5-10 heterocyclyl, OC6-10 aryl, OC50 heterocyclyl, Represents CH2OC1-6 alkyl, CH2SC1-6 alkyl, CH2S aryl,
m represents 2 or 3,
n represents 0 or 1,
p represents 0-2.

  Methods for preparing compounds of the present disclosure and additional compounds suitable for use in the methods disclosed herein are described, for example, by Donde et al., 10, 10-Dialkyl Prostantic Acid Derivatives for the Lower Intramolecular Pressure (US Pat. No. 6, , 875, 787), Donde et al., 10,10-Dialyl Prostanoic Acid Derivatives as Agents for Lowering Intramolecular Pressure (U.S. Patent Publication No. 2004/0235958) 0164992 It can be found in, respectively, incorporated by reference in its entirety herein.

  As used herein, the term “skin defect” refers to a shallow wound that may occur on any area of the body's skin, from but not limited to cosmetic surgery. Includes scars from scars, back, mid-chest, heart, abdomen, caesarean section, pubic area, and joint surgery, or scars from wrinkles, aging, and UV aging, or wrinkles.

  A “shallow wound” can be any area where the structural integrity of the outer surface of the skin has been compromised. Shallow wounds can result from skin incisions, lacerations, abrasions, burns, chemical burns, radiation, chemical poisoning, or punctures. Wounds can be superficial or can extend to deeper layers of the dermis, subcutaneous, deep fascia, muscle, bone, or other internal organs.

  “Scar” refers to fibrous tissue formation (fibrosis) or sclerosis after disease, including various surgeries, injury, burns, irradiation, contact with chemicals, or various infections on all parts of the body, For example, areas of abnormal skin appearance resulting from scleroderma or loss of normal skin components. Scar types include, but are not limited to, hypertrophic scars, recessed scars, and skin streaks. Hypertrophic scars occur when the body overproduces collagen, raising the scars above the surrounding skin. An example of a hypertrophic scar is a keloid scar, which includes preventing recurrence of fibrous tissue growth after resection of an existing keloid scar. Atrophic or depressed scars have a sunk appearance and occur when the underlying support structure in the skin is lost. Skin streak (streaks) is when the skin is stretched rapidly (ie, due to significant weight gain or rapid growth, or after pregnancy) or during the healing process, typically near the joints, Occurs when placed under tension. As used herein, the term “scar” encompasses any type of skin scar resulting from any cause.

  As used herein, the term “wrinkle” refers to habitual facial expressions, age-related collagen and / or loss of elasticity, sun damage, smoking, lack of hydration, and various other Skin folds, ridges, wrinkles, grooves, pits, depressions, or sinking areas that can be caused by factors. Wrinkles can vary from deep wrinkles to fine lines. Wrinkles that occur in any part of the body, particularly wrinkles in the subject's head or neck, are contemplated herein. Wrinkles that can be treated according to the present disclosure include, but are not limited to, an eyebrow groove, an eyebrows fine line, a nasal lip groove, one or more lines under the eye or between the eyebrows, and combinations thereof.

  As used herein, “treatment” means preventing and / or reducing (or eliminating) one or more characteristics of a skin defect, either temporary or permanent. When a composition is administered to treat a wound, the composition promotes normal healing compared to a wound without administration. That is, the size (length, depth, height, and / or width), characteristics, color, and / or texture of the treated wound is more similar to normal non-wound tissue. In this regard, treatment of wounds with the compositions of the present disclosure can prevent scar formation, minimize scar formation, or improve the appearance of scar formation, resulting in wound healing. Further, when the composition of the present disclosure is administered to treat wrinkles, the wrinkles are treated when the appearance or bumps of wrinkles are visually or clinically reduced. That is, the length and / or depth is reduced compared to the wrinkle before treatment. Alternatively, treatment may include wrinkle prevention. In this regard, the composition of the present disclosure can be used to prevent wrinkles from occurring on skins that typically wrinkle, such as the forehead, lips, eyelids, nasal lip, skin under the eyes, or skin between the eyebrows. Can be applied to the area.

  The compositions of the present disclosure can be administered to prevent scar formation not associated with wounds, such as skin striatum, or scarring due to acne, chicken pox, measles, or other medical conditions. In certain embodiments, the compositions of the present disclosure are administered to the skin stretch region to prevent such scar formation. In these embodiments, the composition can be administered to any area of the face, abdomen, chest, arms, legs, buttocks, back, or any other area where the skin is susceptible to scarring.

  The composition may be administered before the occurrence of skin defects, simultaneously with the occurrence of skin defects and / or after the occurrence of skin defects. For example, a composition of the present disclosure may be administered at any time before incision, during surgery, and / or after surgery, and then further administered after surgery where the healing process occurs. In another example, the composition may be administered during pregnancy to prevent skin striatum. Alternatively, the composition may be administered after the occurrence of the defect.

  The composition may typically be administered for 1-7 days, or as long as necessary to achieve the desired result (which may be days to months). The composition can be administered once or several times a day (2, 3, 4 or more times) depending on the desired effect. In certain embodiments, the composition can be administered once every 1, 2, 3, 4, 5, 6, or 7 days. In another embodiment, the composition may be administered more than once every 1, 2, 3, or 4 weeks. Administration may be monthly or bimonthly. Further, the composition can be administered for 1, 2, 3, 6, 9, or 12 months, or longer. In certain embodiments, the composition can be administered continuously to maintain the desired results.

  The compounds of this disclosure can be administered as part of a composition. As used herein, “formulation” and “composition” may be used interchangeably and may refer to a combination of elements presented together for a given purpose. Such terms are well known to those skilled in the art.

  As used herein, “carrier”, “inert carrier”, and “acceptable carrier” may be used interchangeably and are combined with a compound of the present disclosure to provide the desired composition. It may refer to a carrier that may be provided. One skilled in the art will recognize a number of well-known carriers for making specific pharmaceutical and / or cosmetic compositions. Desirably, the carrier is suitable for application to the keratin surface or other areas of the body. Upon application, acceptable carriers are substantially free of adverse reactions with the skin and other keratin surfaces. For example, the carrier can be a lipid-containing cream or a lipid-free cream, a milky suspension or an emulsion in oil or oil-in-water, a lotion, a gel or jelly, a colloidal or non-colloid aqueous or oily solution, paste, aerosol, soluble It may be in the form of a tablet or stick. According to one embodiment, the composition comprises a dermatologically compatible vehicle or carrier. Vehicles that may be employed to prepare the composition may include, for example, an aqueous solution, such as an saline solution, an oil solution, or an ointment. The vehicle further contains a dermatologically compatible preservative, such as benzalkonium chloride, a surfactant, such as polysorbate 80, liposomes or polymers, such as methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and hyaluronic acid. These may be contained and may be used to increase the viscosity.

Examples of additional agents that can be included in the composition include anti-itch agents, anti-fat deposits, anti-scarring agents, and anti-inflammatory agents, anesthetics, anti-irritants, vasoconstrictors, vasodilators, And anti-bleeding agents / hemostatic agents, and pigmentation improving / depigmenting agents, moisturizers, desquamating agents, tension agents, anti-acne agents. Itching inhibitors can include methylsulfonylmethane, sodium bicarbonate, calamine, allantoin, kaolin, peppermint, tea tree oil, and combinations thereof. Anti-fat deposits can include forskolin; xanthine compounds such as but not limited to caffeine, theophylline, theobromine, and aminophylline; and combinations thereof. Anesthetics can include lidocaine, benzocaine, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, tetracaine, and combinations thereof. Anti-scarring agents can include IFN-gamma, fluorouracil, lactic acid-glycolic acid copolymer, methylated polyethylene glycol, polylactic acid, polyethylene glycol, and combinations thereof. Anti-inflammatory drugs can include dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, and derivatives thereof, and combinations thereof. Furthermore, active agents such as epinephrine, thymidine, cytidine, uridine, antipyrine, aminocaproic acid, tranexamic acid, eucalyptol, allantoin, glycerin, and sodium selenite can be included. The formulation further comprises a degradation inhibitor. Degradation inhibitors include glycosaminoglycans (eg, heparin, heparin sulfate, dermatan sulfate, chondroitin sulfate, O-sulfated HA, linamarin, and amygdalin), antioxidants (eg, ascorbic acid, melatonin, vitamins) C, vitamin E), proteins (eg, serum hyaluronidase inhibitors), and fatty acids (eg, saturated C ₁₀ -C ₂₂ fatty acids). In certain embodiments, the additional active agent is an antioxidant. In certain embodiments, the antioxidant comprises vitamin C, such as vitamin C and / or d-alpha-tocopherol polyethylene glycol 1000 succinic acid (TPGS).

  The compositions of the present disclosure are well suited for topical, subcutaneous, intradermal, subdermal, subcutaneous, and transdermal administration. Topical administration involves the use of a composition that is applied to the skin surface at the site of a skin defect to exert a local effect. Accordingly, such topical compositions are those pharmaceutical or cosmetic that are applied externally by direct contact with the treated skin surface such as the face, neck, arms, legs, and / or torso. Including morphological forms. Conventional pharmaceutical or cosmetic forms for this purpose include ointments, coatings, creams, shampoos, lotions, pastes, jellies, sprays, aerosols, etc., more directly depending on the defect being treated and the skin area. It may be applied or applied with a patch or impregnated dressing. The term “ointment” includes formulations (including creams) having an oleaginous base, a water-soluble base, and an emulsion-type base such as petrolatum, lanolin, polyethylene glycol, and mixtures thereof.

  The composition is also suitable for mesotherapy applications. Mesotherapy is a non-surgical cosmetic treatment technique that involves intraepidermal, intradermal and / or subcutaneous injection of the composition. The composition is administered to the epidermis, dermal epidermal junction, and / or dermis in the form of a plurality of small droplets.

  In accordance with the present disclosure, the pharmaceutical or cosmetic composition optionally includes, but is not limited to, emulsifiers, wetting agents, sweetening or flavoring agents, tonicity adjusting agents, preservatives, buffers, antioxidants, flavonoids and the like More than one agent may be included. Useful tonicity modifiers for the pharmaceutical compositions of the present disclosure include salts such as sodium acetate, sodium chloride, potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable tonicity modifiers. It is not limited to. Preservatives useful in the pharmaceutical compositions described herein include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, mercuric phenyl acetate, and mercuric phenyl nitrate. Prepare a pharmaceutical composition using a variety of buffers and means for adjusting pH, including but not limited to acetate buffer, citrate buffer, phosphate buffer, and borate buffer. be able to. Similarly, antioxidants useful in pharmaceutical compositions are well known in the art and include, for example, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Flavonoids are compounds found in plants that are well known for having various beneficial biochemical and antioxidant effects. The subcategories of flavonoids include flavones, flavonols, flavanones, and flavonols. Examples of flavonoids include luteolin, apigenin, tangerine, quercetin, kaempferol, myricetin, fisetin, isorhamnetin, pakipodor, rhamazine, hesperetin, naringenin, eriodictyol, homoeliodictyol, taxifolin, dihydroquercetin, dihydrokemperol, tannic acid Tannins, condensed tannins, and hydrolyzable tannins. It is understood that these substances and other substances known in the art can be included in the pharmaceutical or cosmetic compositions disclosed herein.

  As used herein, the term “therapeutically effective amount” refers to the biological, medical of a subject in need thereof sought by a researcher, veterinarian, physician, or other clinician. Means the amount of a pharmaceutical or cosmetic composition that elicits a cosmetic or cosmetic response. In some embodiments, the subject in need thereof is a mammal. In certain embodiments, the mammal is a human. An effective amount of the compound can be determined by one skilled in the art, but will vary depending on the compound employed, the frequency of application, and the desired result, and is generally from about 0.0000001% to about 50% by weight of the composition, preferably From about 0.001% to about 50% by weight of the total composition, more preferably from about 0.001% to about 30% by weight of the composition. In certain embodiments, the compound is about 0.004% by weight of the composition.

  The compounds described herein may be administered at least in the minimum dose necessary to achieve the desired therapeutic effect. In general, such doses are in the range of about 1 mg / day to about 1000 mg / day, more preferably in the range of about 10 mg / day to about 500 mg / day. In another exemplary embodiment, the compound or compounds is about 0.0001 mg / kg / day to about 100 mg / kg / day or about 0.01 mg / kg / day to about 100 mg / kg / day. A range may be present in the composition or formulation. However, the actual amount of compound administered will in any case take into account the relevant circumstances such as the patient's age and weight, the patient's general health, the severity of skin defects, and the route of administration, Determined by a doctor. In some cases, administration is evaluated on a case-by-case basis.

  Further, the composition may be designed to delay the release of the compound over a given period of time or to carefully control the amount of compound released at a given time during the course of treatment.

  The pH of the composition of the present disclosure can be from about 3 to about 8.0, or from about 6.5 to about 7.5. In certain embodiments, the pH of the formulation is from about 7.0 to about 7.4, or from about 7.1 to about 7.3.

  Certain specific embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects those skilled in the art to employ such modifications as necessary, and the inventor practiced the invention other than those specifically described herein. Is intended. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

  The specific embodiments disclosed herein may be further limited in the claims using the language “consisting of” or “consisting essentially of”. When used in the claims, the transition term “consisting of” in the claims, whether as filed or added with each amendment, Exclude any element, step, or ingredient not specified. The transition term “consisting essentially of” limits the scope of the claims to those that do not substantially affect the particular substance or process and the basic and novel feature (s). Embodiments of the invention so claimed are described or made possible essentially or explicitly herein.

  All references made to patents and publications throughout this specification are individually incorporated herein by reference in their entirety.

  It should be understood that the embodiments of the invention disclosed herein are examples of the principles of the invention. Other modifications that can be employed are within the scope of the present invention. Thus, by way of example and not limitation, alternative structures of the present invention can be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims (26)

A method of treating a skin defect comprising administering a composition comprising a therapeutically effective amount of a compound having the structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof And n is 0-7, X is S or O,
The administration treats the skin defect;
Method. The method of claim 1, wherein R ⁴ is H, R ³ is H, and X is S. The method of claim 1, wherein R ¹ and R ² are CH ₃ . The method of claim 1, wherein R ⁵ is Cl. The compound is
The method of claim 1, wherein   The method of claim 1, wherein the skin defect is a shallow wound, scar, or wrinkle.   The method of claim 1, wherein the composition is administered subcutaneously, subdermally, or transdermally, intradermally, or topically.   7. The method of claim 6, wherein the administration reduces the formation of a type of scar selected from the group consisting of hypertrophic scars, recessed scars, skin streaks, and combinations thereof.   The method of claim 6, wherein the skin defect is a wrinkle.   The method of claim 1, wherein the composition is administered to an area selected from the group consisting of face, neck, arm, torso, back, leg, and combinations thereof.   The method of claim 1, wherein the composition is administered at a time selected from the group consisting of before surgical incision, during surgery, after surgery, and combinations thereof.   The method of claim 1, wherein the administration minimizes scar formation.   The method of claim 1, wherein the administration prevents scar formation.   The method of claim 1, wherein the administration prevents wrinkle formation.   The method of claim 1, wherein the administration reduces the appearance of existing wrinkles.   The method of claim 9, wherein the wrinkle is selected from the group consisting of a groove between eyebrows, a fine line on the eyebrows, a nasal lip groove, a line under the eyes, a wrinkle between eyebrows, and combinations thereof.   The method of claim 6, wherein the cause of the shallow wound is selected from the group consisting of an incision, a laceration, a burn, a chemical burn, an abrasion, a stab wound, and combinations thereof. A method provided for treating shallow wounds comprising administering a composition comprising a therapeutically effective amount of a compound having the structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof And n is 0-7, X is S or O,
The wound heals more normally than without administration of the composition;
Method. Said compound is compound 1:
The method of claim 18, wherein A method of reducing the appearance of wrinkles, comprising administering to said wrinkles a composition comprising a therapeutically effective amount of a compound having the structure:
Where each dotted line represents the presence or absence of a double bond,
R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H and C ₁ -C ₆ linear alkyl;
R ⁵ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl, and R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, a salt thereof, or an amine thereof And n is 0-7, X is S or O,
The appearance of wrinkles is reduced,
Method. The compound is
21. The method of claim 20, wherein   21. The method of claim 20, wherein the composition is administered topically. A method of treating a skin defect comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one EP4 agonist having the structure:
Where
Each of Z _{1 to} Z ₆ is independently C, N, O, or S;
A is — (CH ₂ ) ₆ — or cis —CH ₂ CH═CH— (CH ₂ ) ₃ —, and one or two carbons may be substituted with S or O, or A Is — (CH ₂ ) _m —Ar— (CH ₂ ) _o —, wherein Ar is arylene or heteroarylene, and the sum of m and o is 1 to 4; ₂ may be substituted with S or O;
R ₁ is H, alkyl, cycloalkyl, oxyalkyl, hydroxyalkyl, alkenyl, oxyalkenyl, or hydroxyalkenyl,
R ₂ is alkyl, hydroxyl, halide, or oxo;
J is alkylene, cycloalkylene, oxyalkylene, hydroxyalkylene, fluoroalkylene, or difluoroalkylene;
E is C _1-12 alkyl, R ₃ , or —Y—R ₃ , wherein Y is CH ₂ , S, or O, R ₃ is aryl or heteroaryl,
n is 0 or 1,
The dotted line represents the presence or absence of a bond,
Method. A method of treating a skin defect comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one EP4 agonist having the structure:



A method of treating a skin defect comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one EP4 agonist having the structure:




A method of treating a skin defect comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one EP4 agonist having the structure: